Abstract 439: Detection of aurora kinase A (AURKA) focal amplification in plasma samples of patients with recurrent ovarian cancer

Abstract

Abstract Purpose: Aurora kinases are associated with acquired resistance to therapy in human cancers. We hypothesized that AURKA amplification is a late event in ovarian cancer (OC) progression and that frequency of amplification might be underestimated if assessed in tumor samples collected at the time of initial diagnosis. To test this hypothesis, we determined AURKA amplification levels in patients with recurrent OC and compared those to AURKA amplification levels in the same patients at the time of diagnosis. Methods: Samples were collected from 33 patients with taxane- and platinum-resistant OC enrolled in a first-in-human (FIH) study that evaluated monotherapy with AMG 900, an orally administered pan-aurora kinase inhibitor (NCT00858377). We performed a targeted analysis of the AURKA locus and surrounding regions using next-generation paired-end sequencing (Illumina HiSeq2500 and 100 bp paired-end reads). By using extremely high sequence coverage (average coverage of > 2,000-fold), we were able to detect and quantify circulating tumor DNA (ctDNA) in plasma and to identify chromosomal alterations characteristic of tumor DNA. Sequencing was performed at Personal Genome Diagnostics (PGDx, Baltimore, MD). In addition, we performed AURKA (20q13) / 20q11 FISH in archival FFPE sections from the same patients. The AURKA (20q13) / 20q11 dual color FISH probe kit was purchased from Kreatech (now Leica Biosystems, Buffalo Grove, IL). Amplification states were defined as follows: amplified: AURKA (20q13) / 20q11 signal > 2.0; borderline: AURKA (20q13) / 20q11 signal < 2.0 and > 1.5; non-amplified: AURKA (20q13) / 20q11 signal < 1.5. FISH analyses were performed at Mosaic Laboratories (Lake Forest, CA). Survival analysis was performed using the Kaplan-Meier method. Results: Plasma samples were available from all patients. Analysis of rearrangements surrounding the AURKA locus in plasma samples identified 11 of the 33 patients as AURKA amplified. Archival FFPE sections were available from 27 of the 33 patients, and 21 of these 27 patients were evaluable by FISH for AURKA amplification. FISH only identified 1 patient as AURKA amplified and 1 additional patient as borderline amplified. Patients with AURKA amplification in plasma had received a median (min, max) of 6 (2,18) prior lines of chemotherapy, while patients without AURKA amplification had received a median (min, max) of 3 (1, 14) lines of prior chemotherapy. AURKA amplification as determined in plasma ctDNA at the time of AMG 900 study entry was an indicator of shorter PFS (median 9.4 vs 19.9 weeks; P = 0.04) and OS (median 9.4 vs 27.6 weeks; P = 0.013). Conclusions: Our results suggest that AURKA amplification is a late event in ovarian cancer progression,and that monitoring AURKA focal amplification in plasma ctDNA allows the non-invasive assessment of acquired resistance to cancer therapy. Citation Format: Gloria Juan, Katherine Paweletz, Abraham Anderson, Erick Gamelin, Gregory Friberg, Robert Loberg, Florian Vogl. Detection of aurora kinase A (AURKA) focal amplification in plasma samples of patients with recurrent ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 439.